Airway disease, including asthma and chronic obstructive pulmonary disease (COPD), is a major health burden in the developed world. In 1999, asthma prevalence was reported at approximately 10,500,000 individuals in the U.S. (Mannino et al., MMWR Surveill Summ 51:1-13, 2002). The prevalence of COPD is estimated at over 23 million adults in the USA (Mannino and Braman, Proc Am Thorac Soc 4:502-506, 2007). In aggregate, airway disease affects up to 15% of the U.S. adult population and leads to a combined annual total of greater than 15,000,000 lost work days, greater than 1,100,000 hospitalizations, and more than 120,000 deaths, at an estimated cost burden of over $23 billion annually. A major component of airway disease is airway hyperresponsiveness (AHR), defined as the exaggerated airway constrictive response to external triggers. AHR manifests clinically as wheezing, dyspnea and cough. Since there are also asymptomatic individuals who exhibit AHR in the laboratory setting, the prevalence of AHR exceeds that of airway disease, and has been estimated at 4-35% of the general population (Jansen et al., Respir Med 91:121-134, 1997).
Currently, AHR treatment in airway disease is non-specific and consists of bronchodilators (adrenergic or anticholinergic) and immunosuppressants (corticosteroids). However, these treatments are fraught with significant side effects. Beta-agonist use has been linked to increased mortality from asthma in several studies, summarized in a meta-analysis (Salpeter et al., Ann Intern Med 144:904-912, 2006). Anticholinergic use in COPD has recently been associated with increased mortality from cardiovascular causes in these patients (Singh et al., JAMA 300:1439-1450, 200). Finally, corticosteroids have a number of adverse effects, even when used topically as inhalants (Dahl, Respir Med 100:1307-1317, 2006). Significant reasons for the side effect profile of currently existing AHR treatments are their lack of specificity and their broad, non-targeted mechanism of action. A specific, causative and physiologic treatment of AHR would therefore greatly benefit management of airway disease patients.
Hyaluronan is an abundant extracellular matrix component that has been shown to play a significant role in the response to non-infectious lung injury. Hyaluronan is a non-sulfated glycosaminoglycan that exists as a large polymer of disaccharides (D-glucuronic acid and D-N-acetylglucosamine). Short-fragment hyaluronan (sHA; also known as low molecular weight hyaluronan—LMW-HA) is released in the lung after sterile injury such as bleomycin instillation (Teder et al., Science 296(5565):155-158, 2002) or high-tidal-volume ventilation (Bai et al., Am J Respir Crit. Care Med 172(1):92-98, 2005), and can modify the tissue response to injury.
In addition, hyaluronan has been identified in airway secretions from asthmatics (Sahu and Lynn, Biochem J 173(2):565-568, 1978) and high molecular weight hyaluronan (HMW-HA) can attenuate the bronchoconstrictive response in exercise-induced asthma (Petrigni and Allegra, Pulm Pharmacol Ther 19(3):166-171, 2006). Furthermore, it has been previously demonstrated that hyaluronan mediates both airway inflammation and AHR after environmental pollutant exposure and in several mouse models of asthma (PCT Publication No. WO 2010/068308 and Garantziotis et al., J Biol Chem 284(17):11309-11317, 2009).